ABSTRACT
To evaluate whether two-dose of varicella vaccine would provide a better protection to children from varicella than one-dose, we conducted a 1:3 matched case-control study in children in Qingdao, China. A total of 509 varicella cases aged 6–11 y were collected from the China Information System for Disease Control and Prevention (CISDCP). And 1,527 controls, who did not suffer from varicella, were selected and matched with cases by age and class. The varicella vaccine effectiveness (VE) and corresponding 95% confidence interval (95% CI) were calculated. The vaccination coverage rate of one-dose varicella vaccine in the cases was 52.9%, while for the controls was 59.1%. And the two-dose vaccination rate in the cases and controls were 4.3% and 14.5%, respectively. A statistically significant difference was found in the immunization history between the cases and controls (P < .001).
The overall varicella VE was 56.1% (95% CI: 45.0%–64.9%), and the VE of two-dose vaccination (81.6%, 95% CI: 70.5%–88.4%) was substantially higher than that of one-dose vaccination (44.7%, 95% CI: 31.6%–55.4%). For less than 2 y, 2–4 y, 4–6 y, and more than 6 y after only one-dose vaccination, the varicella VE were 96.6% (95% CI: 75.0%–99.5%), 81.2% (95% CI: 55.6%–92.0%), 60.8% (95% CI: 46.8%–70.2%), and 18.0% (95% CI: 4.3%–35.6%), respectively. The varicella VE gradually decreased over time (P for trend < 0.001). It is recommended that the coverage of varicella vaccine should be increased and two-dose of varicella vaccine should be included in the National Immunization Program of China.
Introduction
Varicella, which is caused by the varicella-zoster virus, is a highly contagious acute respiratory infectious disease.Citation1 This disease, which is characterized by pruritic varicella rashes and systemic papules, commonly occurs in children. The condition usually resolves itself within one week, and severe complications just occur in a few cases. According to the World Health Organization (WHO), there are at least 140 million infections worldwide every year. Besides, the China Information System for Disease Control and Prevention (CISDCP) has stated that the incidence rate of varicella is increasing and that varicella is the leading cause of public health emergencies caused by infectious diseases in children in China.
The varicella vaccine, which was developed in Japan in 1974, has become available worldwide for preventing and controlling varicella.Citation2 The morbidity and mortality of varicella as well as related health care expenses have been substantially reduced in the United States since a universal varicella vaccination program was implemented in 1995.Citation3–5 Despite this success, the outbreak of varicella continues to occur sporadically.Citation6,Citation7 At present, the varicella vaccine has not been introduced into the National Immunization Program of China, and only one-dose immunization schedule of varicella vaccine is adopted in voluntary children aged 1–12 y.Citation8 Although one-dose varicella vaccine could reduce the mortality and morbidity of varicella, it could not prevent the outbreak.Citation9–12
Recently, some studies have been conducted to estimate the protective effect of two-dose of varicella vaccine in children in China.Citation11,Citation13–16 A cohort study carried out by Suo L. et al. suggested that moderate two-dose varicella vaccine coverage was insufficient to prevent a varicella outbreak.Citation11 Another study by Pan X. et al. concluded that two-dose regimen could provide excellent protection against varicella.Citation13 Since 2016, a two-dose schedule of varicella vaccine has been offered in Qingdao, China, but the vaccine effectiveness (VE) has not been fully evaluated. Therefore, we conducted a 1:3 retrospective matched case-control study to estimate and compare the VE of one-dose and two-dose schedules of varicella vaccine in children in Qingdao to provide a scientific basis for developing immunization strategies for varicella.
Materials and methods
Study population and design
In July 2018, a 1:3 retrospective matched case-control study was conducted among primary school students in Qingdao, China. The varicella case was defined as an illness characterized by acute onset of a generalized maculopapular rash but without any other apparent causes.Citation17 All the varicella cases were selected from the CISDCP, were diagnosed by experienced doctors at the local hospitals, and further verified within 48 hours by the staffs at the Centers for Disease Control and Prevention (CDC), Qingdao. The children with chronic skin ailments, including urticaria papulosa and pustular eruptions, were not registered in the CISDCP as varicella cases. The inclusion criteria for cases were as follows: (1) the children were aged 6–11 y and lived in Qingdao, and (2) the children had complete varicella immunization information. The informed consents were brought home from school by children and signed by their parents/guardians.
For each case, three subjects were selected as controls by simple random sampling and were matched with the case by age and class at school. More specifically, the controls were chosen by using lottery method according to their student number. The inclusion criteria for the controls included: (1) the controls had no history of varicella; (2) the controls were matched with cases by age (±1 y); and (3) the controls attended the same class as the cases. The controls who did not have any documented vaccination history or had varicella vaccination incomplete information were excluded from the study. The informed consents were brought home by children to be signed by their parents/guardians.
Vaccination
During 2006–2018, four kinds of domestic varicella vaccines (Changsheng, Baike, Keygen, and Shanghai) were used in Qingdao, China. These varicella vaccines possessed a similar concentration of Oka strain VZV: >2000 plaque formation unit (PFU)/dose (0.5 mL), and the same temperature (2–8°C) was required for cold chain storage and transportation.
Since 2012, Qingdao has made one-dose of varicella vaccine available for children over 12 months old. And in 2016, the two-dose regimen was recommended for children by CDC, Qingdao: the first dose should be provided for children aged 1–2 y old, while the second should be administered at 4–5 y old, with an interval between the first and second dose of 3 y.
Breakthrough
Breakthrough varicella was defined as a case that developed more than 42 d after vaccination, and its clinical symptoms were consistent with the clinical diagnosis of varicella.Citation18 Breakthrough infection rate referred to the proportion of breakthrough infection among children who have received the varicella vaccination.
Data collection
All subjects’ information was obtained from the Qingdao Immunization Program Information System (QIPIS) which was established in 2009. This system incorporates all immunization data of children living in Qingdao. Two researchers (YW and TTX) were responsible for the data collection, such as children’s names, gender, date of birth, dose and date of vaccination, and varicella history. For cases, the additional information, date of onset was also collected.
Statistical analysis
Vaccine effectiveness represents the percent reduction in disease incidence attributable to vaccination and plays an important role in measuring vaccine efficacy. It is calculated using the equation VE = (ARU-ARV)/ARU x 100%, where ARU and ARV are the attack rates in the unvaccinated and vaccinated subjects, respectively. This equation can also be manipulated and expressed as VE = 1 – (ARV/ARU) x 100%, where ARV/ARU is the relative risk (RR). The case-control studies can be used to calculate the odds ratio (OR), which approximates to the RR. Thus, VE can be calculated following the equation: VE = (1-OR) x 100%.
The data were entered into IBM SPSS 21.0 software for statistical analysis, and descriptive statistics were expressed as means ± standard deviation or percentage frequency, as appropriate. The student’s t-test was applied to assess statistically significant differences between groups for continuous variables, and the Pearson chi-square test was adopted to evaluate statistically significant differences between categorical values. Conditional logistic regression analysis was used to calculate the odds ratio (OR) and corresponding 95% confidence interval (95% CI), which was further utilized to estimate the varicella VE (95% CI). The unvaccinated subjects were regarded as the reference group for varicella VE evaluation, and the varicella VE of one-dose (or two-dose) was calculated by comparing one-dose (or two-dose) vaccinated subjects with unvaccinated subjects. The trend chi-square test was performed to estimate the effect of the vaccine over time after vaccination. A P-value < 0.05 was considered as statistically significant.
Results
General demographic characteristics
A total of 2036 subjects were included in the study, including 509 cases and 1527 controls. The mean age of the cases and controls was 7.86 ± 1.36 and 7.84 ± 1.39 y, respectively. There was no significant difference between the case group and the control group concerning gender (P= .870) and age (P= .660).
Varicella vaccination coverage
Of all the subjects, 1414 (69.4%) children were vaccinated against varicella. Among the 509 subjects who contracted with varicella, 218 (42.8%) children did not receive varicella vaccine, 269 (52.9%) children received one-dose vaccination, and 22 (4.3%) children received two-dose vaccination. By contrast, among the 1,527 children in the control group who did not contract varicella, 404 (26.4%) children were unvaccinated against varicella, 902 (59.1%) children received one-dose vaccination, and 221 (14.5%) children received two-dose vaccination (). Statistically significant difference was identified in the varicella vaccine immunization history between the case group and the control group (P< .001).
Table 1. Protective effects of the varicella vaccine on subjects in different groups stratified by age and received dose
Varicella VE
shows the varicella VE among subjects at different ages and doses. The overall varicella VE for children aged 6–11 y was 56.1% (95% CI: 45.0%–64.9%; P< .001), among which the VE of one-dose was 44.7% (95% CI: 31.6%–55.4%; P< .001), while that of two-dose was 81.6% (95% CI: 70.5%–88.4%; P< .001). The varicella VE increased with dose rising. Similar results were obtained for children of different ages. The varicella VE for at least one dose in children aged 6–8 y and 9–11 y was 59.2% (95% CI: 46.5%–69.0%; P< .001) and 48.4% (95% CI: 22.9%–65.4%; P= .002), respectively. Children aged 6–8 y who received one-dose vaccination showed an VE of 48.3% (95% CI: 33.0%–60.1%; P< .001), while the VE of children with two-dose was 80.6% (95% CI: 67.2%–88.5%; P< .001). The protective effect of one-dose and two-dose of varicella vaccine in children aged 9–11 y was 36.3% (95% CI: 7.1%–56.3%; P= .013) and 85.5% (95% CI: 58.2%–95.0%; P< .001), respectively. This demonstrated that the varicella VE decreased with an increase in age.
The interval of one-dose varicella vaccination
Of the children who received one-dose of varicella vaccine, the VE was 96.6% (95% CI: 75.0%–99.5%; P< .001), 81.2% (95% CI: 55.6%–92.0%; P< .001), and 60.8% (95% CI: 46.8%–70.2%; P< .001) in the first 2 y, 2–4 y, and 4–6 y after vaccination, respectively. However, no protective effect was detected at more than 6 y after vaccination (VE = 18.0%, 95% CI: −4.3%–35.6%; P= .110). This clearly illustrated that varicella VE gradually decreased over time (Pfor trend < 0.001) ().
Table 2. Relationship between one-dose varicella vaccine effectiveness and time after vaccination
Breakthrough cases
A total of 1414 subjects received varicella vaccine, and there were 291 (20.6%) breakthrough cases, with the average time interval between vaccination and the onset of varicella was 6.60 ± 2.00 y. More specifically, the average was 0.44 y for one-dose and 10.76 y for two-dose. Among the 1171 subjects who only received one-dose vaccination and the 243 subjects who finished two-dose vaccination, 296 (25.3%) and 22 (9.1%) breakthrough cases were found, respectively. The one-dose vaccinated subjects had a significantly higher breakthrough varicella infection rate than the two-dose vaccinated subjects (χ2 = 23.851, P< .001).
Discussion
Currently, the varicella vaccine is widely available around the world, and it has been proven to be the most effective measure for the prevention and control of varicella.Citation19 At present, the results of studies on the varicella VE ranged from 6.8%Citation20 to 96.2%.Citation21 In our study, we found that the overall varicella VE for children aged 6–11 y was 56.1%, while the varicella VE of one-dose was only 44.7%. The results were similar to the 44.0% of Gao’s study,Citation22 but lower than the 81.0% of a meta-analysis.Citation23 The differences in VE reported in these literatures might be due to the source of cases, age of the subjects, and design of the study.
The Susceptible-Exposed-Infective-Removed (SEIR) model was a classic epidemic model, which reflected the characteristics of infectious disease transmission and predicted its trends by constructing equations.Citation24 By establishing an SEIR model, the study of Pan J. et al. indicated that the protective effect of vaccine showed a positive correlation with the coverage rate. When the coverage rate was 10%, 30%, 50%, 70%, and 90%, the yearly varicella incidence rate dropped 11%, 34%, 57%, 78%, and 92%, respectively.Citation25 A low coverage rate could theoretically lead to an increase in the number of cases in older children and adults for whom the disease was generally much more severe.Citation26 Emergency immunization programs during varicella outbreaks also played an important role in decreasing secondary cases, and the protective effect in the high coverage group was almost twice that of the low coverage group.Citation27 Qingdao did not implement a free vaccination program for children until 2004. In this study, the overall coverage rate for children aged 6–11 y was only 69.4%, which made it difficult to control the occurrence of varicella and reduce breakthrough cases. The coverage rate of the case group in this study was only 57.2%, which was significantly lower than 73.6% for the control group. It suggested that we should continue to strengthen the varicella vaccination program for age-eligible children and increase the coverage rate to reduce the incidence of varicella in the future.
In our study, all the subjects were stratified by age and dose. The VE in the 6–8-y-old group was higher than that in the 9–11-y-old group, and a higher efficacy was observed in the two-dose than in the one-dose group. These results were consistent with the observation reported in another study in Taiwan in 2010.Citation28 However, the long-term response to the varicella vaccination diminished, and the protective effect of the vaccine gradually decreased over time. It could only delay the age of onset and had little impact on controlling the morbidity of older children. Our findings also confirmed previous reports, which stated that the antibody levels in vaccinated children tended to wane with time.Citation29 One-dose of varicella vaccine is insufficient for the provision of an immune barrier for the population, indicating that it is necessary to strengthen the immunization program of varicella vaccine and compensate for single-dose immunity failure and the waning of vaccine-induced immunity.Citation30,Citation31
The vaccination years and breakthrough cases of varicella vaccine were analyzed in this study. We found that the rate of breakthrough infection was 20.6%, compared to the 12.7% and 46.7% that were observed in other studies.Citation10,Citation32 The one-dose vaccinated subjects had a remarkably higher rate of breakthrough varicella infection rate than the two-dose vaccinated subjects (P< .001), signifying that two-dose of varicella vaccine could significantly decrease the rate of varicella breakthrough and increase vaccine efficacy. For the single-dose vaccination, the varicella VE decreased with the time dropping rapidly at 4 y after vaccination and not offering any noticeable protection after 6 y. This was consistent with the median incidence of breakthrough cases at 6.43 y after vaccination. Our analysis provided clear evidence that the protection afforded by one-dose varicella vaccine in children might diminish as time pass, and the incidence of breakthrough disease increased as the post-vaccination time grew longer,Citation29 Initially induced by varicella vaccine, humoral immunity weakened over time, and the one-dose vaccine did not generate sufficient population immunity to prevent breakthrough cases.Citation29,Citation33 Conversely, results indicate that two-dose of varicella vaccine produced a higher level of antibody titer and was more likely to protect against breakthrough disease.Citation30 Since two-dose varicella vaccination produced greater protection than one-dose vaccination, increasing increased two-dose vaccination coverage could produce a more preventive effect.Citation11
In 2006, the Advisory Committee on Immunization Practice (ACIP) in the United States changed its immunization policy by stipulating that two-dose of varicella vaccine should be administered, once at one year old and another between 4 and 6 y old.Citation34 Germany also revised their vaccination program in 2009 to provide two-dose of varicella vaccine.Citation35 During the past few years, studies on two-dose varicella vaccine have been carried out in various provinces across China. These results agreed that two-dose varicella vaccine among children could produce an improved humoral immune response and raise antibody levels, thus enhancing the protection from the disease.Citation14–16 It has been only 4 y since the implementation of the two-dose varicella vaccination program in Qingdao, but according to an analysis of the vaccination situation, the immunization coverage rate of one-dose was 57.5%, while for the two-dose it was only 11.9%. Although the two-dose vaccine had a high protective effect, it had a limited effect on the control of varicella due to a low degree of immunization coverage rate.
Several limitations needed to be considered in this study. First, although strict inclusion and exclusion criteria were applied while selecting eligible subjects in our study, selection bias was still unavoidable. All the varicella cases were clinically diagnosed rather than being confirmed by laboratory testing. Therefore, the children who suffered from subclinical infection without developing characteristic rashes might have been regarded as controls. Besides, rashes caused by insect bites or viral infections might also have been mistaken as varicella, although this would occur infrequently. However, all these misdiagnoses of varicella could result in overestimating or underestimating the VE. Second, the low varicella vaccination coverage in Qingdao might not provide sufficiently high population immunity to prevent varicella outbreaks. Third, in this study, a small number of children were infected with varicella after receiving their second varicella vaccination. The reasons for this were unclear, but it could be due to vaccine failure or waning immunity.Citation13
In conclusion, the varicella VE for the one-dose is relatively low, and the VE decreases significantly with time after vaccination. The use of a two-dose regimen can provide an increased protective effect. Considering the cost-effectiveness of vaccination and the potential complications of contracting varicella, we recommend introducing the two-dose of varicella vaccine into the National Immunization Program. Meanwhile, the coverage rate of the varicella vaccine for school-aged children should be increased.
Authors’ contributions
Conception and design: PH, FY, XFL, JG, SPL.
Acquisition of data: YW, TTX, HL, WCW.
Collecting data: YW, TTX.
Analysis and interpretation of data: PH, JG, SPL.
Writing, review, and/or revision of the manuscript: PH, FY, XFL.
Revising: PH, FY, XFL, JG, SPL.
All authors read and approved the final manuscript.
Acknowledgments
We highly appreciate the help from the school staff for their assistance with the investigation. We are also indebted to the children and their parents/guardians for their participation and cooperation.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
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